Subunit-dependent Inhibition of Human Neuronal Nicotinic Acetylcholine Receptors and Other Ligand-gated Ion Channels by Dissociative Anesthetics Ketamine and Dizocilpine

Background: The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia.

Methods: Heteromeric human neuronal nicotinic acetylcholine receptors (hnAChR channels [alpha]2[beta]2, [alpha]2[beta]4, [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2 and [alpha]4[beta]4), 5-hydroxytryptamine3 (5-HT3), [alpha]1[beta]2[gamma]2S[gamma]-aminobutyric acid type A (GABAA) and [alpha]1 glycine receptors were expressed in Xenopus oocytes, and effects of ketamine and dizocilpine were studied using the two-electrode voltage-clamp technique.

Results: Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitive and voltage-dependent manner. Receptors containing [beta]4 subunits were more sensitive to ketamine and dizocilpine than those containing [beta]2 subunits. The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of [beta]4 subunits were 9.5-29 [mu]M, whereas those of [beta]2subunits were 50-92 [mu]M. Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABAA and glycine receptors were very resistant to dissociative anesthetics.